MAb CC49 reacts with tumor-associated glycoprotein (TAG)-72, a human pancarcinoma antigen. Clinical trials using radiolabeled murine CC49 have shown excellent tumor localization to colorectal, ovarian, and prostate carcinomas. To optimize therapeutic efficacy and minimize toxicity and host immune responses to diagnostic and therapeutic protocols utilizing CC49, studies have focused on the design and translational research of novel recombinant CC49 Ig forms. The metabolic patterns, pharmacokinetic properties, and tumor-targeting ability of CDR-grafted humanized (Hu) and domain-deleted CC49 Igs have been delineated. A humanized CH2 domain-deleted CC49 has been constructed and demonstrates significantly faster plasma clearance and better tumor- targeting than the intact CC49. A single-gene-encoded single-chain Ig with a CH1 domain deletion (HuCC49SCIg-delta-CH1) has shown similar antigen binding and cytotoxic activity as the parent molecule, HuCC49. Collaborative studies are in progress to develop MHC-unrestricted chimeric T-cell receptors (URs) capable of redirecting the antigenic specificity of human T-cells to specific tumor-associated antigens. The antigen receptor, encoded by a single gene, contains the antigen binding site of an anti-tumor Ig and the zeta chain of the CD3 complex of the T-cell receptor. Recently, UR molecules have been derived from the single-gene-encoded HuCC49SCIg-delta-CH1. The CC49-zeta-URs have been transduced by retroviral gene transfer into human CD8+T-cells and CD4+T- cells. In vitro cytolytic activity of the CC49-zeta-UR-T-cells has been demonstrated against TAG-72 positive human tumor cell lines. No cytolytic activity has been observed against TAG-72 negative cell lines. Cytolytic activity of the CC49-zeta-UR-T-cells is retained when the CTL assay is done in the presence of TAG-72 at levels similar to those detected in the sera of 95% of carcinoma patients. A Phase I/II clinical trial to study multiple infusions of CC49-zeta-modified-T-cells in patients with metastatic colon cancer expressing TAG-72 recently has received approval from the Food and Drug Administration. Carcinoembryonic antigen (CEA ) is an Mr 180,000 complex glycoprotein highly expressed in carcinomas of the gastrointestinal tract, breast, ovary, lung and pancreas. Studies are in progress to develop MHC- unrestricted URs for redirection of the specificity of T-cells to CEA positive cells.